Antiangiogenic kringles derived from human plasminogen and apolipoprotein(a) inhibit fibrinolysis through a mechanism that requires a functional lysine-binding site.

Many proteins in the fibrinolysis pathway contain antiangiogenic kringle domains. Owing to the high degree of homology between kringle domains, there has been a safety concern that antiangiogenic kringles could interact with common kringle proteins during fibrinolysis leading to adverse effects in vivo. To address this issue, we investigated the effects of several antiangiogenic kringle proteins including angiostatin, apolipoprotein(a) kringles IV(9)-IV(10)-V (LK68), apolipoprotein(a) kringle V (rhLK8) and a derivative of rhLK8 mutated to produce a functional lysine-binding site (Lys-rhLK8) on the entire fibrinolytic process in vitro and analyzed the role of lysine binding. Angiostatin, LK68 and Lys-rhLK8 increased clot lysis time in a dose-dependent manner, inhibited tissue-type plasminogen activator-mediated plasminogen activation on a thrombin-modified fibrinogen (TMF) surface, showed binding to TMF and significantly decreased the amount of plasminogen bound to TMF. The inhibition of fibrinolysis by these proteins appears to be dependent on their functional lysine-binding sites. However, rhLK8 had no effect on these processes owing to an inability to bind lysine. Collectively, these results indicate that antiangiogenic kringles without lysine binding sites might be safer with respect to physiological fibrinolysis than lysine-binding antiangiogenic kringles. However, the clinical significance of these findings will require further validation in vivo.

Anisoylated plasminogen streptokinase activator complex in acute myocardial infarction: a placebo-controlled arteriographic coronary recanalization study.

Anisoylated plasminogen streptokinase activator complex (APSAC) is a new thrombolytic agent that is of interest because of its ease of administration as an intravenous bolus injection. This report describes the first double-blind, placebo-controlled evaluation of intravenous APSAC for coronary recanalization in acute myocardial infarction. Unequivocal documentation of recanalization was provided by coronary arteriography before and after the drug intervention. Forty patients with acute myocardial infarction underwent coronary arteriography 3.1 +/- 1.2 hours after the onset of symptoms. This demonstrated occlusion of the infarct-related coronary artery in 29 patients who were then randomized to treatment with intravenous APSAC, 30 mg (n = 16), and placebo (n = 13) 3.3 +/- 1.3 hours after the onset of symptoms. Repeat arteriography 90 minutes later demonstrated recanalization of the infarct-related coronary artery in nine patients who had received APSAC compared with only one patient who had received placebo (56 versus 8%, p less than 0.05). The 95% confidence limits for this 48% difference between the groups are 20 to 76%. Arteriography at 3 days showed persistent patency of all recanalized coronary arteries except one (APSAC group) and also showed late recanalization in another four patients, three of whom had received APSAC. In the patients who had a patent infarct-related coronary artery at the initial arteriographic study, patency was maintained throughout the study period regardless of whether the patient was randomized to APSAC (n = 4) or placebo (n = 7). Complications related to APSAC therapy were excessive bruising at the catheterization site in seven patients and minor sensitivity reactions in three.(ABSTRACT TRUNCATED AT 250 WORDS)

Multicenter trial of intravenous anisoylated plasminogen streptokinase activator complex (APSAC) in acute myocardial infarction: effects on infarct size and left ventricular function.

Two hundred thirty-one patients with a first acute myocardial infarction were randomly allocated within 5 h after the onset of symptoms either to treatment with anisoylated plasminogen streptokinase activator complex (APSAC), 30 U over 5 min, or to conventional heparin therapy, 5,000 IU in a bolus injection. Heparin was reintroduced in both groups 4 h after initial therapy at a dosage of 500 IU/kg per day. One hundred twelve patients received APSAC and 119 received heparin within a mean period of 188 +/- 62 min after the onset of symptoms. Both groups were similar in age, location of the acute myocardial infarction, Killip functional class and time of randomization. Elective coronary arteriography was performed on an average of 4 +/- 1.2 days after initial therapy. Follow-up radionuclide angiography and thallium-201 single photon emission computed tomography were performed before hospital discharge. Infarct size was estimated from single photon emission computed tomography and expressed as a percent of total myocardial volume. The patency rate of the infarct-related artery was 77% in the APSAC group and 36% in the heparin group (p less than 0.001). Left ventricular ejection fraction determined from contrast angiography was significantly higher in the APSAC group than in the heparin group. This was true for the entire study group (0.53 +/- 0.13 versus 0.47 +/- 0.12; p = 0.002) as well as for the subgroups of patients with anterior and inferior wall infarction (0.47 +/- 0.13 versus 0.40 +/- 0.11; p = 0.04 and 0.56 +/- 0.10 versus 0.51 +/- 0.11; p = 0.02, respectively). At 3 weeks, the difference remained significant for the anterior myocardial infarction subgroup. A significant 31% reduction in infarct size was found in the APSAC group (33% for the anterior infarction subgroup [p less than 0.05] and 16% for the inferior infarction subgroup [p = NS]). A close inverse relation was found between the values of left ventricular ejection fraction and infarct size (r = -0.73, p less than 0.01). By the end of a 3 week follow-up period, seven APSAC-treated patients and six heparin-treated patients had died. In conclusion, the early infusion of APSAC in acute myocardial infarction produced a high early patency rate, significant limitation of infarct size and significant preservation of left ventricular systolic function, mainly in anterior wall infarction.

Multicenter reperfusion trial of intravenous anisoylated plasminogen streptokinase activator complex (APSAC) in acute myocardial infarction: controlled comparison with intracoronary streptokinase.

The recent establishment of a firm therapeutic role for reperfusion in acute myocardial infarction has stimulated interest in the development of more ideal thrombolytic agents. Anisoylated plasminogen streptokinase activator complex (APSAC) is a new plasminogen activator possessing properties that are promising for intravenous thrombolytic application in acute myocardial infarction. To assess the reperfusion potential of intravenous APSAC, a multi-center, angiographically controlled reperfusion trial was performed. An approved thrombolytic regimen of intracoronary streptokinase served as a control. Consenting patients with clinical and electrocardiographic signs of acute myocardial infarction were studied angiographically and 240 qualifying patients with documented coronary occlusion (flow grade 0 or 1) were randomized to treatment in less than 6 h of symptom onset (mean 3.4 h, range 0.4 to 6.0) with either intravenous APSAC (30 U in 2 to 4 min) or intracoronary streptokinase (160,000 U over 60 min). Both groups also received heparin for greater than or equal to 24 h. Reperfusion was evaluated angiographically over 90 min and success was defined as advancement of grade 0 or 1 to grade 2 or 3 flow. Rates of reperfusion for the two treatment regimens were 51% (59 of 115) at 90 min after intravenous APSAC and 60% (67 of 111) after 60 min of intracoronary streptokinase (p less than or equal to 0.18). Reperfusion at any time within the 90 min was observed in 55 and 64%, respectively (p less than or equal to 0.16). Time to reperfusion occurred at 43 +/- 23 min after intravenous and 31 +/- 17 min after intracoronary therapy. The success of intravenous therapy was dependent on the time to treatment: 60% of APSAC patients treated within 4 h exhibited reperfusion compared with 33% of those treated after 4 h (p less than or equal to 0.01). Reperfusion rates were also dependent on initial flow grade (p less than or equal to 0.0001): 48% (81 of 168) for grade 0 (APSAC = 43%, streptokinase = 54%), but 78% for grade 1 (APSAC = 78%, streptokinase = 77%). APSAC given as a rapid injection was generally well tolerated, although the median change in blood pressure at 2 to 4 min was greater after APSAC than after streptokinase (-10 versus -5 mm Hg). Mean plasma fibrogen levels fell more at 90 min after the sixfold higher dose of APSAC than after streptokinase (to 32 versus 64% of control). Reported bleeding events were more frequent after APSAC but occurred primarily at the site of catheter insertion and no event was intracranial.(ABSTRACT TRUNCATED AT 400 WORDS)

Development and evaluation of anisoylated plasminogen streptokinase activator complex (APSAC) as a second generation thrombolytic agent.

Anisoylated plasminogen streptokinase activator complex (APSAC) was developed as a second generation thrombolytic agent in an attempt to overcome some of the limitations to the intravenous application of streptokinase for coronary artery thrombolysis. Temporary protection of the active site on the plasminogen molecule by acylation allows APSAC to be given by rapid injection, confers semiselectivity for clot (at lower doses) and prolonged fibrinolytic action. These properties may simplify intravenous administration, improve coronary reperfusion response and reduce reocclusion potential. Clinical trials with APSAC, still ongoing, allow the following tentative conclusions: the efficacy of intravenous APSAC appears to be equivalent to that of intracoronary streptokinase, when given within 4 hours of the onset of symptoms of myocardial infarction, and superior to that of intravenous streptokinase, but it is easier to administer. Early APSAC therapy leads to reperfusion rates of 60 to 65% and patency rates of 70 to 80%. Early reocclusion rates (within 24 hours) appear to be as low as or lower than those obtained with other agents. Bleeding complications and allergic manifestations after APSAC are acceptably low and comparable with those of equivalent doses of streptokinase. The potential for mortality benefit after APSAC appears to be high and is undergoing additional study. Thus, APSAC therapy, which can be given by simple injection over 2 to 5 minutes, appears promising as a future first line approach to reperfusion therapy in acute myocardial infarction.

Intracoronary thrombolysis with an acylated streptokinase-plasminogen activator (BRL 26921) in patients with acute myocardial infarction.

The fibrinolytic efficacy and systemic effects on coagulation variables of intracoronary administration of an acylated streptokinase-plasminogen complex (BRL 26921) were assessed in 23 patients with an acute transmural myocardial infarction. The infarct vessel was totally occluded in 22 patients and subtotally stenosed in 1 patient. Reperfusion was achieved in a total of 17 patients (74%), in 2 patients with the use of a guide wire. Reperfusion time in those patients treated with BRL 26921 alone amounted to 42 +/- 37 minutes. Reocclusion occurred in two patients subsequently. Four patients died; in two of these, intracoronary thrombolysis was unsuccessful. Reptilase time increased from 13 +/- 3 to 49 +/- 31 seconds (p less than 0.001), fibrinogen levels decreased from 280 +/- 65 to 126 +/- 76 mg% (p less than 0.001). Factor V decreased from 96 +/- 11 to 53 +/- 26% (p less than 0.001), and factor VIII from 99 +/- 1 to 55 +/- 36% (p less than 0.001). Peripheral hyperplasminemia, defined as a reduction of fibrinogen (less than 100 mg%) with a reduction of factor V and VIII (less than 75%) simultaneously occurred in eight patients. Six (75%) of these 8 patients demonstrated reperfusion, whereas 9 (64%) of 14 patients without peripheral hyperplasminemia were also successfully reperfused. Bleeding complications occurred in two patients who demonstrated hyperplasminemia. Thus, effective intracoronary thrombolysis could be achieved with only minor effects on peripheral coagulation variables in the majority of patients.

The German multicenter trial of anisoylated plasminogen streptokinase activator complex versus heparin for acute myocardial infarction.

A multicenter randomized trial of anisoylated plasminogen streptokinase activator complex (APSAC) versus heparin in patients with acute myocardial infarction of less than 4 hours' duration was undertaken in 19 hospitals. Of the 313 patients, 151 received heparin and 162 APSAC (30 U as intravenous injection). Within 28 days of hospital stay, 19 deaths (12.6%) occurred in the heparin group and 9 deaths (5.6%) in the APSAC group (p = 0.032). After 24 hours, patients in the APSAC group had a significantly lower incidence of cardiogenic shock (3.2 vs 9.5%, p = 0.031), asystole (3.8 vs 10.8%, p = 0.015) and need for resuscitation (5.1 vs 11.5%, p = 0.039). There was no difference in global and infarct-related ejection fraction between the 2 groups. Thus, APSAC favorably influences prognosis and clinical course in hospital.

Limitation of myocardial infarct size and preservation of left ventricular function by early administration of APSAC in myocardial infarction.

In cases of acute myocardial infarction (MI), it has been shown that preserving left ventricular function and limiting infarct size with early reperfusion of the occluded artery by means of a thrombolytic agent could eventually result in a reduced mortality rate. The aim of the APSIM study (anisoylated plasminogen streptokinase activator complex [APSAC] dans l'infarctus du Myocarde) was to demonstrate that early administration of APSAC in patients with recent acute MI could limit the infarct size and preserve left ventricular systolic function. In all, 231 patients with a first acute MI were randomly allocated to either APSAC (30 U over 5 minutes) or to conventional heparin therapy (5,000 IU in bolus injection) within 5 hours of the onset of symptoms. Of these patients, 112 received APSAC and 119 received heparin within a mean period of 188 +/- 62 minutes after the onset of symptoms. The patency rate of the infarct-related artery was 77% in the APSAC group and 36% in the heparin group (p less than 0.001). Left ventricular ejection fraction determined from contrast angiography was significantly higher in the APSAC than in the heparin group. This was true for the entire population (0.53 +/- 0.13 vs 0.47 +/- 0.13, p = 0.002) as well as for the subgroups of anterior and inferior wall infarctions (0.47 +/- 0.13 vs 0.4 +/- 0.16, p = 0.004 and 0.56 +/- 0.11 vs 0.51 +/- 0.09, p = 0.02). At 3 weeks, the difference remained significant for patients with anterior MI.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of intravenous anisoylated plasminogen streptokinase activator complex and intracoronary streptokinase in acute myocardial infarction.

Coronary angiography was used to compare the efficacy of anisoylated plasminogen streptokinase activator complex (APSAC) administered intravenously and streptokinase given by intracoronary infusion in inducing reperfusion in patients with a proven acute myocardial infarction. Forty-two patients received 30 U of APSAC intravenously over 5 minutes and 43 patients received 250,000 IU of streptokinase given via intracoronary infusion over 90 minutes, after occlusion of the infarct-related vessel was demonstrated by angiography. Reperfusion was achieved in 23 (64%) of 36 patients (mean time to reperfusion 46 minutes) treated with APSAC and 25 (67%) of 37 patients (mean time to reperfusion 45 minutes) treated with intracoronary streptokinase, who were angiographically evaluated 90 minutes after the start of treatment. Twenty-four hours after treatment, reocclusion had occurred in 1 (5%) of 22 patients in the APSAC group and in 3 (13%) of 23 patients in the streptokinase group. No major bleeding was observed in either treatment group despite a similar systemic lytic state that lasted for up to 48 hours. Two patients treated with APSAC died after severe left ventricular failure unrelated to therapy. The results indicate that APSAC given intravenously is as effective as streptokinase given intracoronary in producing thrombolysis in acute myocardial infarction. The major advantages of APSAC are its rapid and convenient administration by a single intravenous injection, the low rate of arterial reocclusion and good patient tolerance.

Coronary thrombolysis during acute myocardial infarction by intravenous BRL 26921, a new anisoylated plasminogen-streptokinase activator complex.

The safety and fibrinolytic efficacy of a new anisoylated plasminogen-streptokinase activator complex (APSAC) was tested in 50 patients with acute myocardial infarction (AMI) less than 4 hours in duration. APSAC (30 mg) was given intravenously as a bolus injection 151 +/- 47 minutes after clinical symptoms. Coronary angiography was then performed to assess coronary artery patency: 28 patients had an inferior AMI and 22 an anterior AMI. A patent infarct-related artery was found in 32 patients (64%) on first coronary angiography 66 +/- 21 minutes after administration of APSAC. Subsequent reperfusion was observed in 10 patients after 74 +/- 16 minutes (84%). Bleeding complications or hematomas were observed in 18 patients, of whom 3 required blood transfusions. Marked hypofibrinogenemia was observed within 24 hours in most patients. A control coronary angiogram was recorded in 37 patients (74%) after 25 +/- 19 days and showed reocclusion in 5 patients.

Safety and side effects of anisoylated plasminogen streptokinase activator complex and streptokinase in patients with acute myocardial infarction. Interim report of the IRS II Study.

86 patients with a first myocardial infarction presenting within 6 hours of the onset of symptoms were randomly allocated to treatment with intravenous streptokinase or anisoylated plasminogen streptokinase activator complex (APSAC). Side effects were observed in 34.1% of patients (15 of 44) in the streptokinase group and 23.8% (10 of 42) in the APSAC group. These effects included injection related effects (in 4 patients on streptokinase versus 6 on APSAC) and neurological complications (0 vs 2 patients, respectively). Femoral haematoma accounted for the majority of bleeding events. Death occurred as a consequence of haemorrhage in 2 patients (1 receiving streptokinase and the other APSAC).

Summary of early clinical experience with anisoylated plasminogen streptokinase activator complex in the treatment of acute myocardial infarction.

Preliminary investigations using a single intracoronary dose of APSAC (up to 30U) revealed dissolution of intracoronary thrombi in 59 of 83 patients (71%) with acute myocardial infarction, as indicated by reperfusion of coronary arteries. Reocclusion of arteries occurred in 20.5% of patients. Based on these findings, a subsequent study was undertaken in 302 patients with evidence of recent acute myocardial infarction. Single intravenous bolus doses of APSAC (5 to 30U) produced reperfusion in 79% of patients, with reocclusion occurring in only 9% of patients receiving the higher doses. Adverse effects included an initial hypotension/bradycardia reaction, a later syndrome featuring pyrexia, nausea and vomiting, and bleeding complications, including 4 patients with cerebrovascular accidents. In these early studies APSAC appeared to be as effective as streptokinase, as reported in the literature, and to produce a lower incidence of reocclusion than tissue plasminogen activator.

A randomised placebo-controlled pilot dose-response study with anisoylated plasminogen streptokinase activator complex in acute coronary artery occlusions.

The aim of this study was to determine the dose-response relationship of anisoylated plasminogen streptokinase activator complex (APSAC) by means of a between group double-blind comparison of the new agent and placebo. 50 patients with symptoms of acute myocardial infarction of less than 6 hours duration and whose coronary artery occlusion had been confirmed by coronary angiography were randomly allocated to 5 treatment groups (15, 20, 25 or 30U of APSAC, or placebo) and treatment was given as an intravenous injection over 2 minutes. Angiography was performed again at 15, 30, 45, 60 and 90 minutes and the films were assessed centrally by 2 independent cardiologists. Six patients were excluded from the angiographic analysis, 4 because their angiograms revealed patent arteries before APSAC was administered, 1 patient was excluded because streptokinase had been infused just after randomisation because of cardiogenic shock and 1 because the angiogram was not available due to problems in the film development. Clinical and laboratory examinations carried out for 72 hours after treatment showed that the drug was well tolerated. The reperfusion rates were as follows: placebo, 0/9; APSAC 15U, 5/8; APSAC 20U, 5/9; APSAC 25U, 6/9; APSAC 30U, 5/9. Reperfusion was achieved in 60% of treated patients but no dose relationship was revealed.

An interim report of a double-blind placebo-controlled recanalisation study of anisoylated plasminogen streptokinase activator complex in acute myocardial infarction.

This is an interim report of the initial 36 patients entered into the first double-blind, placebo-controlled invasive arteriographic study of intravenous anisoylated plasminogen streptokinase activator complex (APSAC) for coronary recanalisation in acute myocardial infarction. Coronary arteriography was performed before and 90 minutes after a single intravenous bolus injection of APSAC or placebo given over 2 to 5 minutes. Pretreatment coronary arteriography was performed in 36 patients at a mean time of 189 +/- 75 minutes after the onset of symptoms. 28 patients had occluded infarct-related coronary arteries and were randomised to receive APSAC 30U (n = 15) or placebo (n = 13) by intravenous injection 195 +/- 72 minutes after the onset of symptoms. Coronary arteriography 90 minutes after treatment demonstrated recanalisation of the infarct-related coronary artery in 8 APSAC-treated patients compared with only 1 placebo-treated patient (p less than 0.02). Repeat coronary arteriography 3 days after treatment showed reocclusion in 1 of the 8 APSAC-treated patients and persistent perfusion in the single patient who reperfused on placebo. All patients with patent vessels at pretreatment coronary arteriography (3 APSAC, 5 placebo) remained patent throughout the study period. There were no haemorrhagic complications related to APSAC therapy. These data confirm that APSAC is a safe, effective thrombolytic agent which, when administered by the intravenous route, resulted in a 53% recanalisation rate.

Comparative tolerance and complications in a multicentre trial of intracoronary streptokinase and intravenous anisoylated plasminogen streptokinase activator complex in acute myocardial infarction.

The safety and tolerance data of the preliminary results of a randomised, parallel group, multicentre trial of intracoronary streptokinase and intravenous anisoylated plasminogen streptokinase activator complex (APSAC) in patients with myocardial infarction are presented. The frequency of side effects was similar in the 2 groups. The most frequently encountered side effect was bleeding, overwhelmingly from the groin puncture site from angiography. There was no significant difference between amount or incidence of bleeding complications between the two groups, as measured by number of bleeding episodes, transfusion requirements, or mean drop in haematocrit or haemoglobin.

Safety and tolerance data from the Belgian multicentre study of anisoylated plasminogen streptokinase activator complex versus heparin in acute myocardial infarction.

In the European Multicentre Study (EMS), the safety and efficacy of a single 30U intravenous injection of anisoylated plasminogen streptokinase activator complex (APSAC) was studied in patients with acute myocardial infarction. The present study discusses the Belgian data on safety and tolerance from the EMS study. 87 patients were randomised to treatment with APSAC or heparin. The reperfusion rate was 60.5% (APSAC) versus 20.5% (heparin control), and reocclusion occurred in 21% of the reperfused APSAC patients. Drug-related adverse events consisted of bleeding problems (7 events in patients on APSAC and 1 event in a patient on heparin and moderate allergic reactions (12 events in 9 patients on APSAC and 1 event in a heparin patient). There was 1 drug-related death in the APSAC group (hypovolaemic shock due to central vein puncture during lytic state) which could have been avoided. It is concluded that thrombolytic treatment of acute myocardial infarction with APSAC is effective and safe, as long as the standard precautions for thrombolytic treatment are respected. Bleeding and allergic-type events are infrequent, usually well tolerated and easily treated.

Dose-ranging studies of anisoylated plasminogen streptokinase activator complex. Studies in healthy volunteers and in patients with acute myocardial infarction.

Anisoylated plasminogen streptokinase activator complex (APSAC) is well tolerated when given as an intravenous bolus dose over 2 to 4 minutes. The intravenous administration of 30U was rapidly effective in patients with coronary artery occlusion, with 82% of successfully treated patients responding to the initial APSAC dose after a mean time of about 30 minutes. The plasma fibrinogen and plasminogen concentrations decreased in all patients receiving APSAC 30U, which indicates that APSAC at this dose is not sufficiently fibrin-specific to dissolve thrombi without producing a lytic state. Side effects, complications and mortality were as expected for thrombolytic agents, with only 1 bleeding episode other than at the catheterisation site. Thus, APSAC offers unique advantages of rapid and simple bolus intravenous administration, with reperfusion rates achieved that are similar to those expected for intracoronary streptokinase and for intravenous tissue plasminogen activator.

Intravenous anisoylated plasminogen streptokinase activator complex versus intravenous streptokinase in evolving myocardial infarction. Preliminary data from a randomised multicentre study.

The efficacy of a single intravenous bolus of anisoylated plasminogen streptokinase activator complex (APSAC 30U in 4 to 5 minutes) versus an intravenous infusion of streptokinase (1.5 X 10(6) U in 60 minutes) was assessed in 86 patients with evolving myocardial infarction of less than 6 hours duration in a cooperative randomised study. The patency of the infarct-related artery was assessed by coronary angiography at, on average, 90 minutes after therapy (mean time: APSAC 95 minutes, streptokinase 105 minutes). The treatment groups were similar with respect to sex, age, location of myocardial infarction and the delay from onset of pain to treatment. The 90-minute patency rate (grade 2 to 3) was 71.8% in the APSAC group and 55.8% in the streptokinase group; the difference was not statistically significant. There was no difference between the drop in fibrinogen concentrations in the 2 groups at 3 or 24 hours. The minimal concentration obtained at the first assessment was +/- 0.2 g/L in the streptokinase group and 0.5 g/L in the APSAC group. One patient in the APSAC group, who had a previous meningeal bleeding, had a non-fatal cerebrovascular accident. In a subgroup of 38 patients who had 3 control coronary angiograms at 90 minutes, 24 hours and 3 weeks, the patency rate was 63, 82 and 93%, respectively, in the APSAC group and 48, 88 and 92%, respectively, in the streptokinase group (the difference was not statistically significant). None of the patients in the APSAC group presented with reocclusion, whilst 3 patients in the streptokinase group had reocclusions.(ABSTRACT TRUNCATED AT 250 WORDS)

Reperfusion in acute myocardial infarction. A multicentre randomised trial of early intracoronary streptokinase and intravenous anisoylated plasminogen streptokinase activator complex in the United States.

To compare the reperfusion potential of anisoylated plasminogen streptokinase activator complex (APSAC), administered intravenously, and intracoronary streptokinase (the accepted standard for comparison in the United States), a randomised multicentre reperfusion trial was undertaken in the United States. A preliminary evaluation of results was made, based on the first 93 patients. Patients with acute myocardial infarction were studied angiographically, and those with coronary occlusion grade 0 or 1 were randomised and treated within 6 hours from symptom onset (mean 3 hours 25 minutes) with intracoronary streptokinase (20,000U bolus, then 2000 U/minute), or APSAC (30U over 2 to 4 minutes). Reperfusion was defined by a blinded reader as grade 2 or 3 flow after 90 minutes. Entry characteristics of patients in the 2 groups were comparable. Reperfusion rates were similar [19/39 (49%) of evaluable streptokinase patients and 19/43 (44%) of APSAC patients] and were dependent on the initial occlusion grade [38% of patients with grade 0 (streptokinase = 10/27, APSAC = 13/34), but 71% of patients with grade 1 (9/12, 6/9, respectively); p less than 0.02]. Grade 1 occlusion was present in 30% of patients treated within 4 hours, versus 16% treated at over 4 hours (p = 0.3). APSAC as a 2 to 4 minute infusion was well tolerated, and the change in mean blood pressure was minor (-6 mm Hg). Thus, APSAC and streptokinase provide similar reperfusion results, but APSAC is easier to administer, and shows excellent haemodynamic tolerance.

Anisoylated plasminogen streptokinase activator complex versus placebo. A preliminary multicentre study of safety and early mortality in acute myocardial infarction.

90 patients were enrolled into this preliminary multicentre study of the efficacy and safety of 30 units intravenous anisoylated plasminogen streptokinase activator complex (APSAC) compared with placebo in patients with acute myocardial infarction. 45 patients received APSAC and 45 placebo; the groups were similar for age, weight and site of infarction. There were significantly more women treated with APSAC (p less than 0.02). The mean time to treatment was 3.3 hours after symptoms of myocardial infarction for APSAC and 3 hours for placebo. The 30-day mortality was 7 patients in the placebo group and 1 in the APSAC group (p = 0.058). Adverse events were generally minor and were of similar overall frequency in both groups. There were more haemorrhagic events with APSAC, from which all patients recovered, and more cardiovascular events with placebo including 2 deaths from cardiogenic shock. APSAC showed a trend towards a reduction in 30-day mortality. Experience from this study has led to the initiation of the APSAC in myocardial infarction multicentre mortality study (AIMS).